Thiol-mediated catalysis of nitroglycerin degradation by serum proteins. Increase in metabolism was not accompanied by S-nitrosothiol production

In vitro degradation of nitroglycerin (NTG) in human plasma has been shown to be accelerated significantly by sulfhydryl compounds. The interaction between NTG and N-acetyl-1-cysteine (NAC) in human plasma produces a pharmacologically active S-nitrosothiol, which may be responsible, at least in part, for the in vivo nitrate tolerance-reversing effect of NAC. The mechanism of this thiol-mediated NTG degradation in plasma has not been identified. In this report, we examined the catalytic activity of various plasma proteins toward NAC-mediated NTG degradation and found human serum albumin (HSA) to have the highest catalytic activity among the proteins tested. However, the dinitrate metabolite distribution ratio found with HSA(favoring the 1,3- over the 1,2-isomer) was substantially different from that observed with human plasma (where equal amounts of both dinitrates were produced). In addition, the HAS-catalyzed degradation of NTG did not lead to enhanced formation of S-nitrosothiol. These findings therefore argue against a predominant role exerted by HSA in the thiol-mediated NTG metabolism in plasma. The HSA-mediated catalysis of NTG was partially blocked by pretreatment with NAC followed by a thiol-alkylating agent, suggesting that the catalytic mechanism was due, in part, to the conversion of disulfide linkages within the HSA structure to reactive sulfhydryl groups.